JPH05247013A - Novel oxime derivative of aminothiazolyl acetic acid and preparation thereof - Google Patents

Abstract

PURPOSE: To obtain a new compd. useful as a synthesis intermediate of new compds. and having a very good antibiotic activity against penicillin-resistant staphylococcus bacteria, E. coli Klebsiella, Salmonella, Proteus bacteria, etc.

CONSTITUTION: The compd. is a compd. of formula I [wherein R' is a 2-4C alkyl; A is H or an alk (alk is a 1-4C alkyl), OR' is in syn position], e.g. syn isomer of ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyimino acetate. The compds. of the formula I, e.g. a compd. of formula II among them, is obtd. by reacting thiourea with a compd. of formula III and then treating with a base. The compd. of the formula I is useful as an intermediate for prepn. of an oxime deriv. of a novel 7-aminothaiazolyl acetoamide cephalosporanic acid of formula IV (wherein R is H or trityl; A' is H, an alkali metal, alkaline earth metal, etc.).

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel oxime derivative of aminothiazolylacetic acid and a process for producing the same.

More specifically, the present invention provides the following general formula I '.

[Chemical 6] (Here, R represents a hydrogen atom or a trityl group, R'represents an alkyl group having 2 to 4 carbon atoms, and A '
Represents a hydrogen atom or an equivalent amount of an alkali metal, an alkaline earth metal, magnesium or an organic amino base, and the group O
R ′ is in the syn position) and a novel 7-aminothiazolylacetamide cephalosporanic acid oxime derivative production intermediate and methods for their production.

Compounds of the above general formula I'defined as having the syn isomeric form have the following general formula defined as having the anti isomeric form:

[Chemical 7] The inventors of the present invention completed the present invention by knowing that it exhibits a higher antibacterial activity against Gram-positive and negative bacteria and other bacteria than the above compounds.

[0004]

DETAILED DESCRIPTION OF THE INVENTION The subject of the invention is therefore the following intermediates of the general formula I, which are intermediates for the preparation of the compounds of the general formula I ′.

[Chemical 8] (Wherein R'represents a saturated alkyl group having 2 to 4 carbon atoms, A represents a hydrogen atom or alk, and
alk represents an alkyl group having 1 to 4 carbon atoms, the group OR ′ being in the syn position). Among these compounds, especially the following formula IV

[Chemical 9] (Wherein R ′ has the above meaning and alk is an alkyl group having 1 to 4 carbon atoms);

[Chemical 10] (Wherein R ′ has the above meaning).

In the above formula, the alkyl group represented by R'includes ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl groups. Further, the alkyl group represented by A is methyl,
Mention may be made of ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl groups. In particular, the subject of the invention is the compounds described in the examples below, in particular the 2-
It is in the syn isomer of ethyl (2-amino-4-thiazolyl) -2-ethoxyiminoacetate.

A subject of the invention is also a process for the preparation of compounds of formula IV as described above, which comprises thiourea and a compound of formula III

[Chemical 11] (Wherein R ′ has the meaning given above and alk represents an alkyl group having 1 to 4 carbon atoms) and treated with a base to give the desired compound of formula IV Consists of getting. Alternatively, treating a compound of formula IV with a base and then an acid gives the following formula

[Chemical 12] The acid of

In a preferred method of carrying out the above process, the base used to obtain the compound of formula IV is potassium acetate. However, alkali metal carbonates and acid carbonates or dilute soda or potassium can be used. The base used to saponify the compound of formula IV is preferably caustic soda, but other bases such as caustic potash or barita can also be used. The acid used to isolate the free acid is preferably dilute hydrochloric acid, but acetic acid or formic acid can also be used.

Further, the following formula IV

[Chemical 13] The compound of formula VI

[Chemical 14] (Where alk has the meaning given above) is treated with an alkylating agent to give a compound of formula VII

[Chemical 15] Of a compound of formula VI
II

[Chemical 16] Prepared by reacting this compound with thiourea and then with a base. A compound of formula VI
The alkylating agent used to convert the compound of I is
Preferred are alkyl halides such as chloride, bromide or iodide or alkyl sulfates. The brominating agent used to convert the compound of formula VII to the compound of formula VIII is preferably bromine. The base used after reacting the compound of formula VIII with thiourea is preferably an alkali metal carbonate or acid carbonate. However, dilute soda or potassium or potassium acetate can also be used.

It has been found that the configuration of the compounds of formula IV depends on several parameters involved in the preparation of these compounds. Thus, the reaction of thiourea with a compound of formula III can be carried out in an aqueous solvent such as aqueous acetone or aqueous ethanol or at ambient temperature with a substantially stoichiometric amount of thiourea in a very short time, on the order of 1-3 hours. It has been demonstrated that when carried out by reacting over time, or when all of the above conditions are combined, the syn isomer is obtained.

The amino group of the compounds of formula I of this invention can be protected by amino protecting groups well known to those skilled in the art. For example, an example in which a trityl group is used as the protective group is shown below. First, the following formula IV

[Chemical 17] A compound of the formula (wherein R ′ and alk have the meanings given above) is treated with a functional derivative of the trityl group to give a compound of the formula V

[Chemical 18] (Wherein R ₁ represents a trityl group and R ′ has the above-mentioned meaning), and further the compound of formula V is converted into a base,
It is then treated with acid to give the following formula II

[Chemical 19] Can be obtained. The functional derivative of the trityl group is preferably trityl chloride, used in the presence of triethylamine or other trialkylamines, methylmorpholine or other tertiary amino bases such as pyridine. The base used to saponify the compound of formula V is preferably caustic soda, but other bases such as caustic potash or barita can also be used. The acid used to isolate the acid of formula II is preferably dilute hydrochloric acid, but acetic acid or formic acid can also be used. It has been demonstrated here that the configurations of compounds V, II etc. obtained from compounds of formula IV can be retained during the synthesis.

The above-mentioned oxime derivative of 7-aminothiazolylacetamide cephalosporanic acid of the syn-formula of the general formula I'is represented by the following formula

[Chemical 20] 7-aminocephalosporanic acid of the formula II

[Chemical 21] (Wherein R ₁ represents a trityl group) is reacted with an acid (syn isomer) or a functional derivative of this acid to give a compound of formula Ia

[Chemical formula 22] (Wherein R ₁ and R ′ have the meanings given above), optionally the compound of formula Ia is hydrolyzed in an acid medium to give a compound of formula Ib

[Chemical formula 23] And optionally can be prepared by salting a compound of formula Ia or Ib by conventional methods. This preparation was found to maintain the syn configuration of the compound of formula II throughout the synthesis.

In the above process, 7-aminocephalosporanic acid is treated with a functional derivative of an acid of formula II, such as an anhydride or acid chloride. The acid anhydride has the formula II
It can be formed in situ by reacting the acid with an alkyl chloroformate or dicyclohexylcarbodiimide. Other halides or other alkyl chloroformates, dialkylcarbodiimides or other anhydrides formed in situ by the action of other dicycloalkylcarbodiimides can also be used. Other acid derivatives such as acid azides, activated acid amides or activated acid esters such as hydroxysuccinimide, esters formed by p-nitrophenol or 2,4-dinitrophenol can also be used. .. When the reaction of 7-aminocephalosporanic acid is carried out with the halide of the acid of general formula II or with the anhydride formed by isobutyl chloroformate, the reaction is preferably carried out in the presence of a basic reagent. .. As the basic agent, for example, alkali metal carbonate or N-methylmorpholine, pyridine or trialkylamine such as triethylamine can be selected. Acid hydrolyzing agents acting on the compound of formula Ia may include formic acid, trifluoroacetic acid or acetic acid. These acids can be used in anhydrous form or as an aqueous solution. The compounds of formula Ia or Ib can be salted by conventional methods. Salt formation may be achieved, for example, by adding to these acids an inorganic base such as sodium or potassium hydroxide or sodium bicarbonate or a saturated or unsaturated aliphatic carboxylic acid such as diethyl acetic acid, ethylhexanoic acid or especially acetic acid. It can be produced by reacting a salt of The preferred salt of the aforementioned acids is the sodium salt. Similarly, salt formation can be produced by reacting an organic base such as triethylamine.

As mentioned above, the compound of the general formula I'is
On the one hand against Gram-positive bacteria such as Staphylococcus and Streptococcus, especially against penicillin-resistant Staphylococcus bacteria, and on the other hand against Gram-negative bacteria, especially against coliforms, Grebsiella, Salmonella and Proteus bacteria. And has very good anti-substance activity. These properties make the compound pharmaceutically acceptable for the treatment of infections caused by sensitive microorganisms, in particular for example staphylococcal sepsis, malignant facial or cutaneous staphylococcal infections, purulent dermatitis, putrefaction. Ulcer or purulent ulcer, anthrax, cellulitis,
It is suitable for use as a medicament for the treatment of staphylococcal infections such as erysipelas, early acute influenza or post-influenza staphylococcal infections, bronchopulmonary inflammation and pulmonary suppuration. In addition, these pharmaceutically acceptable compounds are
It can be used as a medicament for the treatment of colibacillosis and related infectious diseases, infectious diseases caused by Proteus, Klebsiella and Salmonella bacteria, and other diseases caused by Gram-negative bacteria.

[0014]

EXAMPLES Examples of the present invention will be shown below, but these do not limit the present invention in any way.

Example 1 : 2- (2-Tritylamino-4-thiazolyl) -2-ethoxyiminoacetic acid, syn Isomer Step A : Ethyl 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetate a ) 19.4 g of ethyl gamma-chloro-alpha-oximinoacetoacetate are placed in 60 cc of acetone and 14.3 cc of diethyl sulfate. The whole is cooled in an ice bath for 10 minutes, 5
Add 5 cc of 2N soda over 30 minutes, then add 4
Stir for 0 minutes. b) To this reaction medium was added 7.6 g of thiourea, which was heated at 55 ° C. for 20 minutes, the acetone was driven off, the residue was dissolved in ethyl acetate, 6.9 g of potassium carbonate was added and the whole was added. Stir, decant, extract with ethyl acetate, dehydrate and concentrate to dryness. 17.4 g of residue are separated off and chromatographed on silica eluting with ether. Recover the desired compound, dissolve in isopropyl ether, vacuum filter, wash, dry,
2.8 g of the expected compound is obtained. MP = 129 ° C. The resulting compound has the syn configuration. Step B : 2- (2-tritylamino-4-thiazolyl)
Ethyl-2-ethoxyiminoacetate 3.16 g of the compound obtained in step A, 6 cc of dry dimethylformamide, 12 cc of methylene chloride and 1.
Place 89 cc of triethylamine under inert gas. The mixture is cooled to -15 ° C and 3.98 g of trityl chloride are added slowly. Leave the whole for half an hour and increase the temperature
Raise to 10 ° C and then keep the whole at ambient temperature for 3 1/2 hours. 13 cc of 1N hydrochloric acid is added, and the whole is stirred, decanted, washed with 1N hydrochloric acid, and then washed with water. 7. Extract with methylene chloride, dehydrate, concentrate to dryness, 7.
89 g of crude residue are obtained. The resulting compound has the syn configuration. Step C : 2- (2-tritylamino-4-thiazolyl)
2-Ethoxyiminoacetic acid 7.89 g of a mixture of the compound obtained in Step B, 40 cc of dioxane and 19.5 cc is heated at 110 ° C. for 1 hour. The mixture is vacuum filtered, washed with an ether-dioxane mixture, then ether alone and dried.
6.25 g of sodium salt was obtained, which was dissolved in 60 cc of methylene chloride and 20 cc of 1N hydrochloric acid, the two phases were stirred, 20 cc of methanol was added, the whole was decanted, washed with water and methylene chloride-methanol mixture. Extracted with water, dehydrated and concentrated, and 5.85 g of pure 2- (2-
Tritylamino-4-thiazolyl) -2-ethoxyiminoacetic acid is isolated. The resulting compound has the syn configuration. NMR (60 MHz, DMSO) ppm: 6.7 (proton of thiazole ring)

Reference Example 1 : 3-acetoxymethyl-7-
[2 (2-Amino-4-thiazolyl) -2- (ethoxyimino) acetamido] cef-3-em-4-carboxylic acid, syn isomer Step A : 3-acetoxymethyl-7- [2- (2- Tritylamino-4-thiazolyl) -2- (ethoxyimino) acetamido] ceph-3-em-4-carboxylic acid 3.4 g of 2- (2-tritylamino-4-thiazolyl obtained in step C of example 1 ) -2-Ethoxyiminoacetic acid,
The syn isomer is taken up in 34 cc of methylene chloride, the suspension is cooled, 970 mg of dicyclohexylcarbodiimide are added, the whole is washed with methylene chloride and stirred for 1 hour at ambient temperature. Vacuum filter the dicyclohexylurea. The filtrate was cooled to −20 ° C. and 1.02 g of 7-aminocephalosporanic acid was added to 18 cc of methylene chloride and 1.0.
A solution prepared by dissolving 6 cc of triethylamine (-20
Chilled to ℃) at once. Let the whole thing heat for one and a half hours,
Add 1.8 cc of acetic acid and 9 cc of 1N hydrochloric acid, stir the whole, decant, wash with water, extract with methylene chloride, dehydrate and concentrate to obtain 4.56 g of the desired compound. The resulting compound has the syn configuration. Step B : 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (ethoxyimino) acetamido) ceph-3-em-4-carboxylic acid Obtained in 4.56 g of Step A. 23 cc of compound
% Aqueous formic acid, heat at 55 ° C. for 15 minutes, then dilute with water (30 cc) and vacuum filter triphenylcarbinol. The filtrate is concentrated to dryness, dissolved in water, stirred, vacuum filtered, washed and dried to give 116 mg of impure product. The filtrate is concentrated to give a secondary yield of 674 mg of crystalline product. 790m in total
g. Perform the following purification. 1.063 g of crude product 5
Make a paste with cc water, heat at 70 ° C. for 5 minutes, cool, stir for half an hour, vacuum filter, wash, dehydrate,
815 mg of purified product are obtained. This 815mg
Was dissolved in 2 cc of water and 3 cc of acetone, insoluble matter was vacuum filtered with slight heating, 3 cc of water was added, the whole was heated to 60 ° C., nitrogen was blown in to expel the acetone, and the resulting granular The product is vacuum filtered, washed with water and then with ether to isolate 438 mg of the desired compound. Analysis : C ₁₇ H ₁₉ O ₇ N ₅ S ₂ Calculation: C% 43.49 H% 4.08 N% 14.92 S% 13.6
6 Found: C% 44.5 H% 4.4 N% 14.8 S% 13.3 This compound has the syn configuration. NMR (60 MHz, DMSO) ppm: 2.05 (OA
c), 6.75 (proton of thiazole ring)

Example 2 : 2- (2-Tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetic acid,
syn Isomer Step A : Ethyl 2-acetyl-2- (1-methylethoxyimino) acetate Add 39.8 g of ethyl 2-acetyl-2-hydroxyiminoacetate to 200 cc of pure acetone. The whole is cooled in an ice bath, 52 g of potassium carbonate are added, then 25 cc of 2-iodopropane are added in half an hour. Then, the whole is stirred for 2 hours, 800 cc of water and 500 cc of methylene chloride are added, the whole is stirred, decanted, extracted with methylene chloride, dehydrated, vacuum filtered and concentrated to obtain 41.5 g of the desired compound. Let go. Step B : 4-Bromo-2- (1-methylethoxyimino) acetylacetate 41.5 g of the compound obtained in the above step are placed in 190 cc of methylene chloride containing a trace amount of p-toluenesulfonic acid. Stir the whole and then add 11.9 cc of bromine to 5
A solution of 0 cc in methylene chloride is introduced at ambient temperature within 1 hour. Stir the whole, add ice cold water,
The whole is decanted, extracted with methylene chloride, washed with ice-cold water, concentrated and 55 g of the expected derivative are isolated. Step C : 2- (2-amino-4-thiazolyl) -2-
Ethyl (1-methylethoxyimino) acetate 14.9 g of thiourea and 105 cc of ethanol and 105
cc water and then 55 g of the compound prepared in Step B in 55 cc of ethanol to prepare a solution of 40
Add in minutes. Stir the whole at ambient temperature for two and a half hours, 22
0 cc of 10% aqueous sodium carbonate solution was added, and the whole was stirred, vacuum filtered, washed, dried, 42.15.
g crude product is isolated and chromatographed on silica eluting with ether. Fractions rich in the desired compound are collected, then concentrated, the crystals are dissolved in isopropyl ether, vacuum filtered and washed to give 10.75 g of the desired compound. The resulting compound has the syn configuration. Step D : 2- (2-tritylamino-4-thiazolyl)
Ethyl-2- (1-methylethoxyimino) acetate 11 g of the compound obtained in step C were mixed with 20 cc of dry dimethylformamide, 40 cc of methylene chloride and 6.2.
cc in a mixture with triethylamine. The mixture is cooled, 13.2 g of trityl chloride are added slowly, the whole is stirred for 2 1/2 hours, 43 cc of 1N hydrochloric acid is added, the whole is stirred and decanted, washed with 40 cc of water and extracted with methylene chloride. After dehydration, vacuum filtration and concentration to dryness, 27.7 g of the expected compound are obtained. The resulting compound has the syn configuration. Step E : 2- (2-Tritylamino-4-thiazolyl)
2- (1-Methylethoxyimino) acetic acid 27.7 g of a mixture of the compound obtained in step D, 150 cc of dioxane and 65 cc of 2N soda are brought to reflux. The sodium salt crystallizes out, the mixture is cooled,
Vacuum filter, wash with 1: 1 ether / dioxane mixture and dry to obtain 16.85 g of crude sodium salt. 1
Dissolve 5.9 g of this sodium salt in a mixture of 15.9 g of dimethylformamide, 100 cc of water and about 500 cc of water, add 30 cc of 2N hydrochloric acid, drive off methanol, dilute the residue with water and vacuum filter. Wash,
Dried and 9.8 g of the viscous product obtained were dissolved in 220 cc of a 50:50 methylene chloride / methanol mixture,
Concentrate to dryness, dissolve in ether, triturate, vacuum filter the crystals, wash and dry. 4.9 g of the expected acid are obtained. MP about 170 ℃. 300 mg of the crude product was dissolved in 2 cc of methylene chloride and 1 cc of methanol, the whole was diluted with water and methylene chloride, then stirred, the crystals were vacuum filtered, washed with methylene chloride, then washed with water and dried, 230 mg of pure compound for analysis is isolated. Analysis : Calculation: C% 68.77 H% 5.34 N% 8.91 S% 6.8 Found: C% 68.6 H% 5.5 N% 8.8 S% 6.8 The resulting compound has the syn configuration.

Reference Example 2 : 3-acetoxymethyl-7-
[2- (2-Amino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido] cef-3-em-
4-Carboxylic acid, syn isomer Step A : 3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido] cef-3-em-4 -Carboxylic acid 4.89 g of 2- (2-Tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetic acid, obtained in step E of Example 2, syn isomer under argon atmosphere to 1
Add to 3.5 cc of dimethylformamide. After dissolution, the solution is cooled in an ice bath and 1.62 g of dicyclohexylcarbodiimide dissolved in 16 cc of methylene chloride is added. Dicyclohexylurea crystallizes out.
The mixture is stirred in an ice bath, vacuum filtered, washed with methylene chloride and dried to isolate 1.424 g dicyclohexylurea. The filtrate is cooled in a methanol-ice bath and then a solution of 1.41 g of 7-aminocephalosporanic acid in 30 cc methylene chloride and 1.45 cc triethylamine is added. Stir the whole at ambient temperature for 3 hours, add 20 cc of 1N hydrochloric acid, stir the whole, decant and extract with methylene chloride,
Dehydrate and vacuum filter to give 9.05 g of the desired and initial compound mixture. This is dissolved in methylene chloride and crystallization is started with stirring, the crystals are vacuum filtered, washed and dried to give 1.6 g of the first pure compound. The filtrate is concentrated to dryness and the residue is dissolved with isopropyl ether with vigorous stirring to isolate 4.91 g of the expected compound, an insoluble viscous product. The resulting compound has the syn configuration. Step B : 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido] cef-3-em-4-carboxylic acid Step A of 4.91 g. 30 cc of the crude product obtained in
Add to 0% aqueous formic acid. The whole is stirred in a water bath at 60 ° C., diluted with water, the resulting triphenylcarbinol is vacuum filtered, washed with water and dried to separate 1.39 g of triphenylcarbinol. The filtrate is concentrated to dryness, washed with water, ground, vacuum filtered, washed with water, dried, 80
0 mg of the expected compound is obtained. 972 mg of crude compound 4
Dissolve in cc methanol, dilute it with 20 cc ether, vacuum filter the insolubles, wash, dry, 40
4 mg of the expected pure acid is obtained for analysis. MP about 2
00 ° C. Analysis : Calculation: C% 44.71 H% 4.38 N% 14.48 S% 13.2
6 Found: C% 44.5 H% 4.5 N% 14.1 S% 13.2 This compound has the syn configuration. NMR (60 MHz, DMSO) ppm: 2.01 (CH ₃
CO), doublet 9.46J = 8HZ (CONH), 6.
7 (proton of thiazole ring)

Reference Example 3 : 3-acetoxymethyl-7-
[2- (2-Amino-4-thiazolyl) -2-ethoxyiminoacetamide] cef-3-em-4-carboxylic acid, anti isomer Step A : 2- (2-tritylamino-4-thiazolyl)
Ethyl 2-hydroxyiminoacetate, anti isomer 11.5 g of anti isomer 2- (2-amino-4-)
Thiazolyl) -2-hydroxyiminoethyl acetate, 90
Mix cc of dry dimethylformamide and 24 cc of triethylamine. Then 47.6 g of trityl chloride were introduced in small portions over half an hour, the whole was allowed to heat spontaneously for two and a half hours, with 150 cc of 2N hydrochloric acid and 60%.
Add 0 cc of water. The whole is stirred for 15 minutes, pasted 3 times with ether, dissolved in a mixture of methanol, triethylamine and water, stirred, vacuum filtered, washed and dried to separate 60.2 g of the expected compound. 3.
4 g of crude product are recrystallized from a methylene chloride-methanol mixture to give 3 g of pure compound. MP = 260 ° C. Step B : 2- (2-tritylamino-4-thiazolyl)
Ethyl 2-ethoxyiminoacetate, anti isomer 11.5 g of the compound obtained in step A, 5.85 g of potassium carbonate and 25 cc of dry dimethylformamide are combined. The whole is cooled to 15 ° C., 16.7 cc of ethyl sulphate are added and the whole is left at ambient temperature for 4 hours, 4
20 cc of water and 250 cc of ethyl acetate were added, and the whole was stirred, decanted, washed with water, extracted with ethyl acetate, dehydrated, vacuum filtered, dissolved in ethanol, crystallized, washed to form a paste. , Dried, 66 g
To obtain the desired compound. MP = 165 ° C. This compound can be recrystallized as follows. 797 mg to 50:
Dissolve in 50 methylene chloride / ethanol mixture, vacuum filter the solution, concentrate to evaporate methylene chloride, recrystallize the product, vacuum filter, wash, dry and give 596 mg of pure compound. To separate. Step C : 2- (2-tritylamino-4-thiazolyl)
2-Ethoxyiminoacetic acid, anti isomer 7.29 g of the compound prepared in Step B is mixed with 45 cc dioxane and 9 cc 2N soda. The whole is heated to 50 ° C. in a water bath with stirring for 1 hour 50 minutes, then cooled, the crystallization is started in ice-cold water, the crystals are vacuum filtered and washed to give 4.2 g of sodium salt. This salt was dissolved in 50 cc of methylene chloride, 40 cc of water and 11 cc of 1N hydrochloric acid, then stirred, decanted, extracted with methylene chloride, washed, dehydrated, vacuum filtered and concentrated to dryness. The product is dissolved in 50 cc of ether, stirred and the crystals are vacuum filtered and washed with ether to give 3.27 g of the expected compound. MP = about 200 ° C. (decomposition) NMR (60 MHz, CDCl ₃ ) ppm: 7.66 (proton of thiazole ring), 7.36 (proton of trityl group) Step D : 3-acetoxymethyl-7- [2- ( 2-Tritylamino-4-thiazolyl) -2-ethoxyiminoacetamido] cepha-3-em-4-carboxylic acid, anti
Isomers 4.1 g of the acid obtained in step C, 36 cc of tetrahydrofuran, 27 cc of methylene chloride and 0.99 cc of N-methylmorpholine are mixed under argon. The mixture is cooled to −20 ° C. and 1.17 cc of isobutyl chloroformate are introduced dropwise. The whole is left at this temperature for 3 minutes, cooled to -35 ° C. and 2.45 g of 7-aminocephalosporanic acid are added to 4.5 cc of methylene chloride and 2.5.
Add a mixture dissolved in 2 cc of triethylamine. The whole is allowed to spontaneously heat for two and a half hours, the solvent is expelled and the distillate is dissolved to pH 1-2 by mixing methylene chloride, water and 1N hydrochloric acid. The whole is extracted with methylene chloride, washed, dried, vacuum filtered, concentrated, dissolved in ethyl acetate, diluted with isopropyl ether, stirred,
Vacuum filtered, washed, dried and 4.87 g of desired compound
Get the anti isomer. Purification is performed as follows.
Dissolve 4.87 g of the above product in 10 cc of ethyl acetate with heating, slowly dilute the solution with isopropyl ether, stir, vacuum filter, wash and dry to obtain 4.53 g of the purified compound. obtain. Step E : 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido] cef-3-em-4-carboxylic acid, anti isomer 4.27 g of step D. The purified compound obtained is added to 20 cc of 50:50 aqueous formic acid. 6 this mixture in a water bath
Heat to 0 ° C, stir for 20 minutes, cool, dilute with water,
Stir for 10 minutes, then vacuum filter triphenylcarbinol and wash with water to give 1.44 g. Ethanol is added and the whole is concentrated under vacuum. The residue was dissolved in ethanol, the ethanol was redissolved under vacuum, 30 cc of water was added to the residue, the resulting mixture was stirred in a bath of ice water for 1 hour, vacuum filtered, washed with water and dried, 2.0
6 g of expected product is obtained. Purification is performed as follows.
2.06 g of the above is dissolved in 5 cc of 10% aqueous sodium bicarbonate solution and 5 cc of water. The cloudy liquid was vacuum filtered, washed with water, and pure formic acid was added dropwise until the pH reached 3 to 4, and the obtained crystals were vacuum filtered after 12 hours at ambient temperature, washed with water, dried, and 1.73 g of the pure compound. To get MP = about 200 ° C. (decomposition) NMR (60 MHz, DMSO) ppm: 2.04 (CH ₃
CHO) 7.5 (proton of thiazole ring)

Reference Example 4 : 3-acetoxymethyl-7-
[2- (2-Amino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido] cef-3-em-
4-carboxylic acid, anti isomer step A : 2- (tritylamino-3-thiazolyl) -2
Ethyl-(1-methylethoxyimino) acetate, anti isomer 6.86 g of anti prepared according to Step A of Reference Example 3
The isomers ethyl 2- (2-tritylamino-4-thiazolyl) -2-hydroxyiminoacetate, 3.51 g potassium carbonate, 15 cc dimethylformamide and 7.7 cc isopropyl iodide are placed under an argon atmosphere. The mixture is left for 4 hours and a half, 250 cc of distilled water and 150 cc of ethyl acetate are added, and the whole is stirred,
Decant, wash, extract with ethyl acetate, dehydrate, vacuum filter, concentrate to dryness, dissolve in ethanol,
Start crystallization, vacuum filter, wash and paste with ethanol to give 3.26 g of the expected compound. MP = 182 ° C. Step B : 2- (2-tritylamino-4-thiazolyl)
-2- (1-Methylethoxyimino) acetic acid, anti isomer 6.8 g of the compound obtained in step A is added to 41 cc of dioxane and 8.15 cc of 2N soda. The whole is heated to 55 ° C. in a water bath for 2 hours, then cooled to 9.5 cc
4. Add 2 N hydrochloric acid to give a pH of 2-3, drive off dioxane, crystallize the residue, dilute with water, stir, wash, paste with ether, dry, 5.
87 g of expected product is obtained. MP = 240 ° C. (decomposition) NMR (CDCl ₃ , 60 MHz) ppm: 7.66 (proton of thiazole), 7.31 (trityl group) Step C : 3-acetoxymethyl-7- [2- (2-tritylamino) -4-thiazolyl) 2- (1-methylethoxyimino) acetamido] cef-3-em-4-carboxylic acid, anti isomer 5.66 g of the acid obtained in step B was 48 cc of tetrahydrofuran, 48 cc of methylene chloride. And 1.32 cc
Of N-methylmorpholine. The whole is dissolved by heating, cooled to -20 ° C, 1.56 cc of isobutyl chloroformate is added, the whole is left for 10 minutes between -20 ° C and -10 ° C, then cooled to -35 ° C, then 3.
A solution of 26 g of 7-aminocephalosporanic acid in 60 cc of methylene chloride and 3.36 cc of dry triethylamine is introduced all at once. Heating the whole, 3
Stir for 30 minutes, drive off the solvent, make sure to dissolve the residue in ethyl acetate, dilute the whole with isopropyl ether, stir, vacuum filter, wash, dry,
5.42 g of expected product is obtained. Dissolve 5.82 g of the compound obtained by the above method in 20 cc of ethyl acetate by heating, dilute it with 200 cc of isopropyl ether, dry and purify to separate 4.82 g of the desired compound. Step D : 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido] cef-3-em-4-carboxylic acid,
anti isomer 3.62 g of compound obtained in step C and 16 cc of 50
Mix -50 aqueous formic acid. 60 minutes of the mixture for 20 minutes
Heat to 0 ° C., then cool, add 16 cc of water, stir whole and vacuum filter the triphenylcarbinol formed, wash with water and dry to obtain 1.23 g. The mother liquor was concentrated to dryness under vacuum and dissolved in ethanol, then ethanol was removed under vacuum, dissolved in water, stirred, started to crystallize by cooling, the resulting crystal-gumous mixture was vacuum filtered, Wash with water, dry and isolate 1.68 g of crude desired compound. A pure sample is obtained as follows. 2 g of the compound was dissolved in 5 cc of 10% aqueous sodium bicarbonate solution and 5 cc of water, the solution was stirred for 10 minutes, vacuum filtered, washed with water, formic acid was added until pH = 3, and the whole was mixed in an ice bath to 1 Stir for a while, vacuum filter, wash with water, heat and dissolve the gum in 10 cc of ethanol, cool with ice water, vacuum filter, wash with ethanol, then wash with ether. 748 mg of purified compound are obtained. further,
The formation of crystalline deposits was observed in the filtrate which was diluted with ether without precipitation, the crystals were vacuum filtered and washed with an ethanol-ether mixture, then ether. 177 mg of pure crystalline compound anti isomer are obtained. MP = about 200 ° C. (decomposition) NMR (DMSO, 60 MHz) ppm: 7.46 (proton of thiazole ring), 4.43 (third proton of isopropyl group)

Pharmacological properties of compounds prepared starting from the compounds according to the invention Method of dilution with inhydro in active liquid medium A set of test tubes is prepared in which the same amount of sterile nutrient medium is distributed. .. The test compound is dispensed into each tube in increasing amounts and then each tube is inoculated with the strain. After incubation for 24 hours (24H) or 48 hours (48H) at 37 ° C in an incubator, inhibition of growth is assessed by light transmission. This is the minimum inhibitory concentration MIC (μ
(expressed in g / cm ³ ). The test compound used was the compound of Reference Example 1, ie, 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamide] cef-3-em-4-carboxylic. The compound of Reference Example 3, which is an acid, syn isomer and corresponding anti isomer, and the compound of Reference Example 2, namely, 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (1-Methylethoxyimino) acetamido] cef-3-em-4-carboxylic acid, a compound of Reference Example 4 which is a syn isomer and a corresponding anti isomer. The following results were obtained.

[0022]

[Table 1]

[0023]

[Table 2]

Claims (5)

[Claims] 1. The following general formula I: (Wherein R ′ represents an alkyl group having 2 to 4 carbon atoms, A represents a hydrogen atom or alk, and alk
Represents an alkyl group having 1 to 4 carbon atoms, the group OR ′ being in the syn position). 2. The following formula IV: (Wherein R'is an alkyl group having 2 to 4 carbon atoms, alk is an alkyl group having 1 to 4 carbon atoms, and the group OR 'is in the syn position). Item 1. The compound according to Item 1. 3. The following formula: The compound according to claim 1, which is a compound of the formula (I) wherein R'is an alkyl group having 2 to 4 carbon atoms and the group OR 'is in the syn position. 4. 2- (2-Amino-4-thiazolyl)-
The compound according to claim 1, which is a syn isomer of ethyl 2-ethoxyiminoacetate. 5. The following formula IV: (Wherein R'is an alkyl group having 2 to 4 carbon atoms, alk represents an alkyl group having 1 to 4 carbon atoms, and the group OR 'is in the syn position). A method comprising thiourea and the following formula III: (Wherein R'represents an alkyl group having 2 to 4 carbon atoms and alk represents an alkyl group having 1 to 4 carbon atoms), and after treatment with a base, Process for the preparation of compounds of formula IV, characterized in that the desired compound of formula IV is obtained.